Omeprazole formulation

ABSTRACT

A stable pharmaceutical pellet formulation that employs a core containing omeprazole or a pharmaceutically acceptable salt of omeprazole and lysine or arginine. The pellet core is directly enteric coated without a separating layer being applied between the core and the enteric coating.

BACKGROUND OF THE INVENTION

The present invention relates to a stable formulation of omeprazole. Itis well known that omeprazole is sensitive to acidic conditions andafter contact with an acid, omeprazole will degrade and will notfunction in its intended manner. Initially, alkaline materials wereadded to a core of omeprazole and later an enteric coating was appliedover the core to prevent the omeprazole from contacting the acidic pHconditions of the stomach. This approach is satisfactory if the productis administered within a short time after it is manufactured but if theproduct is stored under ambient conditions, the acidic residue of theenteric coating appears to degrade the omeprazole before it isadministered to a patient. To solve this problem, the prior art has useda separate layer of a coating agent to coat a pellet core which containsomeprazole and an alkaline material which is thereafter coated with theenteric coating. This technique is described in U.S. Pat. No. 4,786,505.In addition WO 96/24338 discloses the use of an in situ formedinterlayer that is based on the reaction of an aqueous enteric coatingmaterial with an alkaline material in the core.

This dual layer coating technique requires the application of twoseparate functional coating operations which increases the length of themanufacturing process and the cost of the product. The applicants havesurprisingly discovered a coating system which avoids the need to use acoating layer to separate the omeprazole core from the enteric coatinglayer in an omeprazole dosage form. The separate coating system is basedon the combined use of an enteric coating agent which is applied to apelletized core or a granular core of omeprazole as a suspension in asuitable solvent.

The applicants have also surprisingly discovered that arginine or lysinecan be used as a pH stabilizing agent

SUMMARY OF THE INVENTION

The present invention provides a novel stable pharmaceutical compositionof omeprazole for oral administration which consists essentially of:

(a) a core of omeprazole or a pharmaceutically equivalent salt, a fillerand an alkaline material selected from the group consisting of lysineand arginine; and

(b) a single layer of coating on said core which comprises a layer of anenteric coating agent applied from an organic based solvent coatingsystem.

The core of the pharmaceutical composition can be in the form of acompressed tablet which is further comprised essentially of a surfaceactive agent, and a binder. Alternatively, the pharmaceuticalcomposition can have a pelleted core which is further comprisedessentially of an inert core component, a surface active agent and abinder.

Accordingly, it is a primary object of this invention to provide apharmaceutical dosage formulation of omeprazole which is stable uponprolonged storage, is stable when administered to a patient and iscapable of providing the desired therapeutic effect.

It is also an object of this invention to provide a pharmaceuticaldosage form of omeprazole which is bioequivalent to dosage forms ofomeprazole which have an intermediate layer of an inert coatingmaterial.

It is also an object of this invention to provide a stable dosage formof omeprazole which may be produced without the need to provide anintermediate coating layer that separates the omeprazole containing corefrom the enteric coating layer.

These and other objects of the invention will become apparent from areview of the appended specification.

DETAILED DESCRIPTION OF THE INVENTION

The omeprazole formulation of the invention is preferably based on acore of omeprazole or pharmaceutically equivalent salt, a filler and analkaline material selected from the group consisting of arginine orlysine; and a single layer of coating on said core which comprises alayer of an enteric coating agent applied from an organic solvent basedsystem. The Omeprazole core can either be pelleted or tabletted asdescribed herein.

In the case of both the pelleted form and the tabletted form of the corea filler is used. A filler is used as a granulation substrate. Sugarssuch as lactose, dextrose, sucrose, maltose, or microcrystallinecellulose and the like may be used as fillers in either the pellet orthe granulation composition. In the case of the pelleted form the fillermay comprise from 20 to 90 wt % and preferably 65-85 wt % based on thetotal weight of the drug layer composition. In the case of the tablettedform the filler may comprise from 20 to 60 wt % and preferably 20 to 40wt % based on the total weight of the granulation. In the case of thetabletted form of the invention a tablet disintegrant may be added whichcomprises corn starch, potato starch, croscarmelose sodium, crospovidoneand sodium starch glycolate in an effective amount. An effective amountwhich may be from 3 to 10 wt % based on the total weight of thegranulation.

In the case of both the tabletted form and the pelleted form of the corean alkaline agent that is either lysine or arginine is used as astabilizer. In the case of the tabletted form a level of from 20 to 60wt % and preferably 30 to 55 wt % based on the weight of the granulationmay be employed. In the case of the pelleted form a level of from 0.5 to10 wt % and preferably 1 to 3 wt % based on the weight of the pellet maybe employed.

In the case of the pelleted form and the tabletted form of the inventionan enteric coating agent is placed over the core. In both cases theenteric coating may comprise an acid resisting material which resistsacid up to a pH of above about 5.0 or higher which is selected from thegroup consisting of cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, polyvinyl acetate phthalate,carboxymethylethylcellulose, Eudragit L (poly(methacrylic acid,methylmethacrylate), 1:1 ratio; MW (No. Av. 135,000—USP Type A) orEudragit S (poly(methacrylic acid, methylmethacrylate, 1:2 ratio MW (No.Av. 135,000—USP Type B) and mixtures thereof.

The enteric coating agent may also include an inert processing aid in anamount in the case of the tabletted form from 15 to 55 wt % andpreferably 20 to 45 wt % based on the total weight of the acid resistingcomponent and the inert processing aid. In the case of the pelleted formthe inert processing aid is preferably in an amount from 5 to 50 wt %and most preferably 10-20 wt %. The inert processing aids include finelydivided forms of talc, silicon dioxide, magnesium stearate etc. Typicalsolvents which may be used to apply the acid resisting component-inertprocessing aid mixture include isopropyl alcohol, acetone, methylenechloride and the like. Generally the acid resistant component-inertprocessing aid mixture will be applied from a 5 to 20 wt % of acidresisting component-inert processing aid mixture based on the totalweight of the solvent and the acid resistant component-inert processingaid.

In the case of both the tabletted form and the pelleted form of theinvention omeprazole or a pharmaceutically equivalent salt is used inthe core. In the tabletted formulation the omeprazole may comprise from5 to 70 wt % and preferably 10 to 30 wt % of the granulation. In thepelleted form the Omeprazole may comprise from 10 to 50 wt % andpreferably 10 to 20 wt % of the drug layer composition.

A surface active agent is used in both the tabletted and the pelletedform of the invention. The surface active agent may be anypharmaceutically acceptable, non-toxic surfactant. Suitable surfaceactive agents include sodium lauryl sulfate, polysorbate 20, polysorbate40, polysorbate 60, polysorbate 80 and the like. The surface activeagent may be present at a level of from 0.1 to 5 wt %. In the case ofthe tabletted form the surface active agent is preferably 0.20 to 2.0 wt% based on the total weight of the granulation. In the pelleted form thesurface active agent is preferably 0.20 to 2.0 wt % of the total weightof the drug layer composition.

The binder is used in both the tabletted and the pelleted form of theinvention. The binder may be any pharmaceutically acceptable, non-toxicpharmaceutically acceptable binder. The binder is preferably a watersoluble polymer of the group consisting of polyvinyl alcohol,polyvinylpyrrolidone, methylcellulose, hydroxypropyl cellulose,hydroxymethyl cellulose and the like. A water soluble binder ispreferred which is applied from an aqueous medium such as water at alevel of from 0.1 to 10 wt % and preferably from 0.25 to 7.5 wt % ofbinder based on the total weight of the granulation.

In the case of the tabletted form of the invention a granulation isformed by contacting the alkaline agent, the omeprazole, the surfaceactive agent and the binder with a medium which may comprise any lowviscosity solvent such as water, isopropyl alcohol, acetone, ethanol orthe like. When fluids such as water are employed, this will usuallyrequire a weight of fluid which is about three times the weight of thedry components of the coating composition.

After the granulation is formed and dried, the granulation is tablettedand the tablets are directly coated with the enteric coating agent. Acolor imparting agent may be added to the enteric coating agent mixtureor a rapidly dissolving seal coat containing color may be coated overthe enteric coating agent layer provided that the seal coat iscompatible with and does not affect the dissolution of the entericcoating layer. The rapidly dissolving seal coat may comprise Opadry pinkwhich comprises approximately 91 wt % hydroxypropyl methylcellulose(E-6), color and 9 wt % polyethylene glycol which is applied as a 8-15%w/w solution in purified water. In addition the color may be provided asChromateric which is available from Crompton & Knowles. This productcontains water, talc, TiO₂, triethyl citrate, propylene glycol,synthetic red iron oxide, potassium sorbate, xanthan gum, sodium citrateand synthetic yellow iron oxide. If desired, conventional sugar basedseal coats may be used which contain FDA certified dyes.

In the case of a pelleted form the invention is preferably based onpellets having a core forming inert component which may comprise astarch or sugar sphere such as non-pareil sugar seeds having an averagesize of 14 to 35 mesh, preferably about 18 to 20 mesh. The core forminginert component is coated with a formulation which comprises Omeprazole,a surface active agent, a filler, an alkaline material that is eitherlysine or arginine and a binder, which are collectively referred to asthe drug layer composition. The core forming inert component is employedat 1:1 to 5:1 and preferably from 2:1 to 3:1 weight ratio to the druglayer composition.

The cores are formed by spraying the non-pareil seeds with an aqueous ornon-aqueous suspension which contains the alkaline agent, theomeprazole, the surface active agent and the binder. The suspensionmedium may comprise any low viscosity solvent such as water, isopropylalcohol, acetone, ethanol or the like. When fluids such as water areemployed, this will usually require a weight of fluid which is aboutseven times the weight of the dry components of the coating composition.

After the cores are dried, the cores are coated with the enteric coatingagent. A color imparting agent may be added to the enteric coating agentmixture or a rapidly dissolving seal coat over the enteric coating agentlayer provided that the seal coat is compatible with and does no affectthe dissolution of the enteric coating layer.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

Examples 1 to 5 describe a tabletted form of the invention and Example 6describes a pelleted form of the invention.

EXAMPLE 1

Granulation.

A granulation containing omeprazole is formed in a fluid bed coaterusing a top spray granulation forming suspension containing omeprazole,micronized to 95% less than 15 microns, 5% w/w of the total amount ofL-arginine, polyvinyl pyrrolidone, sodium lauryl sulfate and purifiedwater which is sprayed onto a mixture of microcrystalline cellulose, 95%w/w of the total amount of L-arginine and sodium starch glycolate. Theformulation for making the granulation has the following composition:

povidone, USP (Plasdone K90) 100.0 g sodium starch glycolate 100.0 gsodium lauryl sulfate, NF/USP 6.0 g microcrystalline cellulose(AvicelPH101) 965.6 g L-arginine, USP/FCC 1020.0 g omeprazole, USP(micronized) 340.0 g purified water, USP 1100.0 g

Tabletting.

The granulation is tabletted into tablets containing 20 mg of omeprazoleby first mixing the omeprazole granules with glyceryl monostearate:

omeprazole granules 118.0 g glyceryl monostearate (Myvaplex) 6.0 g

Tabletting tools: 0.2812″

target weight : 124 mg/tab target hardness : 7 Kp LOD of granules : lessthan 3%

Enteric Coating.

An enteric coating is applied to prepare enteric coated tablets asfollows:

omeprazole tablets 124.0 g (prepared above) hydroxypropylmethylcellulose 14.7 g phthalate talc 4.2 g acetyl tributyl citrate 2.9g acetone 148.0 g isopropyl alcohol 148.0 g

The solid coating materials were dissolved in the acetone and isopropylalcohol and this solution was coated onto the omeprazole tablets using aperforated pan

Seal Coat:

A seal coat was applied to the enteric coated tablets as follows:

Enteric coated tablet 146.0 g Opadry II pink 4.5 g Water 450.0 g

The seal coat was applied onto the enteric coated omeprazole tabletsusing a perforated pan coater.

EXAMPLE 2

Granulation.

A granulation containing omeprazole is formed in fluid bed coater usinga top spray granulation forming suspension containing omeprazole,micronized to 95% less than 15 microns, 2.68% w/w of the total amount ofL-arginine, polyvinyl pyrrolidone, polysorbate 80 and purified waterwhich is sprayed onto a mixture of microcrystalline cellulose and 95.0%w/w of the total amount of L-arginine. The formulation for making thegranulation has the following composition:

mg/tablet povidone, USP (Plasdone K90) 5.88 polysorbate 80 (Tween 80)0.58 L-arginine, USP/FCC 60.0 omeprazole, USP (micronized) 20.0microcrystalline cellulose (Avicel PH102) 25.54 purified water, USP n/a

Tabletting.

The granulation is tabletted into tablets containing 20 mg of omeprazoleby first mixing the omeprazole granules with glyceryl monostearate:

omeprazole granules 112.0 mg glyceryl monostearate (Myvaplex) 6.8 mgcrospovidone XL 16.2 mg Tabletting tools: 0.2812″ target weight : 135mg/tab target hardness : 7 Kp LOD of granules : less than 3%

Enteric Coating.

An enteric coating was applied to prepare enteric coated tablets asfollows:

omeprazole tablets 135.0 mg (prepared above) Eudragit L30D-55 14.0 mgcolor (Chromateric) 7.0 mg 1M NaOH (to adjust pH to 5.0)qs na Purifiedwater qs na

The solid coating materials were dispersed in the water and this mixturewas coated onto the omeprazole tablets using a perforated pan.

EXAMPLE 3

Granulation.

A granulation containing omeprazole is formed in fluid bed coater usinga top spray granulation forming suspension containing omeprazole,micronized to 95% less than 15 microns, 5.0% w/w of the total amount ofL-arginine, polyvinyl pyrrolidone, sodium lauryl sulfate and purifiedwater which is sprayed onto a mixture of microcrystalline cellulose and95.0% w/w of the total amount of L-arginine. The formulation for makingthe granulation has the following composition:

mg/tablet povidone, USP (Plasdone K90) 5.0 sodium lauryl sulfate 0.3L-arginine, USP/FCC 60.0 omeprazole, USP (micronized) 10.0 gmicrocrystalline cellulose (AvicelPH102) 24.7 purified water, USP n/a

Tabletting.

The granulation is tabletted into tablets containing 10 mg of omeprazoleby first mixing the omeprazole granules with glyceryl monostearate:

omeprazole granules 100.0 mg glyceryl monostearate (Myvaplex) 5.0 mgsodium starch glycolate 5.0 mg Tabletting tools: 0.2812″ target weight :110 mg/tab target hardness : 7 Kp LOD of granules : less than 3%

Enteric Coating.

The tablets were coated with the same enteric coating that was appliedto the tablets in Example 2.

EXAMPLE 4

Granulation.

A granulation containing omeprazole is formed in fluid bed Coater usinga top spray granulation forming suspension containing omeprazole,micronized to 95% less than 15 microns, 5.0% w/w of the total amount ofL-arginine, polyvinyl pyrrolidone, sodium lauryl sulfate and purifiedwater which is sprayed onto a mixture of microcrystalline cellulose and95.0% w/w of the total amount of L-arginine. The formulation for makingthe granulation has the following composition:

mg/tablet povidone, USP (Plasdone K90) 5.88 polysorbate 80 0.60L-arginine, USP/FCC 60.0 omeprazole, USP (micronized) 20.0 crospovidoneXL 5.88 microcrystalline cellulose 25.54 purified water, USP n/a

Tabletting.

The granulation is tabletted into tablets containing 20 mg of omeprazoleby first mixing the omeprazole granules with glyceryl monostearate:

omeprazole granules 117.9 mg glyceryl monostearate (Myvaplex) 6.1 mgTabletting tools: 0.2812″ target weight : 124 mg/tab target hardness : 7Kp LOD of granules : less than 3%

Enteric Coating.

The tablets were coated with the same enteric coating that was appliedto the tablets in Example 1.

EXAMPLE 5

The granulation of Example 1 was prepared and tabletted into tabletscontaining 20.0 mg of omeprazole. These tablets were coated as follows:

Enteric Coating.

An enteric coating was applied to prepare enteric coated tablets asfollows:

omeprazole tablets 126.00 mg (prepared above) Eudragit L30D-55 17.00 mg1M NaOH (to adjust pH to 5.0)qs na acetyl tributyl citrate 1.70 mg talc3.80 mg polysorbate 80 1.50 mg Purified water qs na

The solid coating materials were dispersed in the water and this mixturewas coated onto the omeprazole tablets using a perforated pan. A sealcoat was applied using the procedure of Example 1.

EXAMPLE 6

In the case of a pharmaceutical formulation with a pelleted omeprazolecore, the core is comprised of omeprazole, a surface active agent, afiller, an alkaline material and a binder.

Omeprazole activated pellets (sodium free) are prepared as follows:13.650 kg of Purified water is dispensed into a suitably sized stainlesssteel container. L-Arginine Base (0.210 kg), Lactose Anhydrous, NF (1.75kg) and Povidone (Plasdone® K-90) (0.056 kg) is added to the purifiedwater while homogenizing at full speed (about 5,000 rpm). Homogenizingis continued until the materials are completely dissolved. Polysorbate80, NF (0.044 kg) is added to the solution while homogenizing at a lowerspeed (700-3300 rpm) to avoid excess foaming.

The material is homogenized until dissolved completely. Half of thesolution (7.855 kg) is transferred into a 5-10 gallon stainless steelcontainer. The original container is hereafter referred to as “containerA” and the new container is henceforth referred to as “container B.”Micronized omeprazole 95% less than 15 microns (0.980 kg) is added tocontainer A while homogenizing at a lower speed (700-3300 rpm) to avoidexcess foaming. The Omeprazole is allowed to disperse into the solutioncompletely and then homogenized for another 10 minutes. The homogenizeris replaced with a mechanical stirrer and the suspension is continuouslystirred throughout the coating process. When approximately three fourthof the omeprazole suspension in container A is consumed, 0.980 kg ofmicronized omeprazole is added to container B while homogenizing at alower speed (700-3300) to avoid excess foaming. The Omeprazole isallowed to disperse in the solution completely and homogenization iscontinued for another 10 minutes. The homogenizer is replaced with amechanical stirrer and the suspension is continuously stirred throughoutthe coating process. 9.98 kg of sugar spheres are added to a fluidizedbed coater and preheated until the product reaches 40-45° C. The drugsuspension from containers A and B are sprayed onto the spheres. Theatomization pressure is between 1.5 to 3.5 bar and the pump rate is2-100 ml/min. The spray rate does not exceed 20 ml/min in the first twohours to avoid agglomeration of the sugar spheres. The coatingsuspension is transferred to a smaller container to facilitate stirringwhen the surface of the coating suspension reaches the stirring blade.After the coating suspension has been consumed the pump is stopped andthe fluidization is continued in the fluidized bed coater with the heatoff until the product temperature drops below 32° C.

The pellets are then transferred to a fluidized bed coater into a 50° C.oven (45-55° C.). The pellets are dried until the moisture content ofthe pellets is not more then 2.5%. The pellets are separated intodifferent size fractions by using a SWECO Separator equipped with 14 and24 mesh screens. The pellets are collected in doubled polyethylene linedplastic containers and stored with desiccant.

Enteric Coating Process

10.844 kg of isopropyl alcohol, USP is dispensed into a suitably sizedstainless steel container. 10.844 kg of acetone is added to theisopropyl alcohol. 1.683 kg of hydroxypropyl methylcellulose phthalate(Hypromellose 55, Substitution type 200731) and cetyl alcohol, NF (0.084kg) are added to the solution while homogenizing at full speed until allthe materials are dissolved completely. The homegnizer is then removedand replaced with a mechanical stirrer.

Talc (1.683 kg) is added while stirring. The talc is mixed until fullydispersed in the solution and the mixing is continued throughout theentire coating process. A fluidized bed coater is preheated to 32° C.The omeprazole active pellets (11.550 kg) are loaded into the fluidizedbed coater and preheated until the temperature reaches 30° C.

The coating suspension is sprayed on the pellets using a producttemperature of 25-35° C., an atomization pressure of 1.5 to 3.0 bar anda pump rate of 200-300 ml/min. The coating suspension is transferred toa smaller container to facilitate stirring when the surface of thecoating suspension reaches the stirring blade.

After the coating suspension has been consumed the coated pellets aredried in a fluidized bed coater for 20 minutes using the same coatingconditions except lowering the atomization pressure to 2 bars or below.The coated pellets are discharged into double polyethylene bags. Thepellets are separated into different size fractions by using a SWECOseparator equipped with 14 and 24 mesh screens. The pellets which arelarger than 14 mesh and smaller than 24 mesh are rejected. The pelletsthat passed through the 14 mesh and retained on the 24 mesh are retainedin polyethylene bags.

Blending

Omeprazole enteric coated pellets (Sodium Free), blended are prepared asfollows:

14.400 kg of omeprazole enteric coated pellets (Sodium free) arecharged, into a blender. Talc, USP (0.225 kg) is sprinkled on top of thepellet bed and then blended at 28 rpm for 5 minutes. 0.2 to 0.5 grams ofeach sample is withdrawn into separate vials from the blender. Theblended pellets are unloaded into plastic containers lined with doublepolyethylene. The excess talc is screened off using a SWECO separatorequipped with a 24 mesh screen. The pellets are collected in containerslined with double polyethylene bags and stored with desiccant.

Encapsulation

An encapsulation room is prepared in which the relative humidity is inthe range of 35-65% and the temperature is in the range of 15-25° C.Omeprazole enteric coated pellets (Sodium Free) blended are encapsulatedusing the following equipment and guidelines. A capsule machine modelMACOFAR MT-20 is prepared for the procedure placing the machine settingat 4, using capsule machine size part 1, capsule magazine 1. Thetarget-filled capsule weight is 457.15 mg. If the total weight is notwithin 3% of the target weight, further adjustment must be performed.Capsule fill verification is performed at twenty minutes intervals onten individual capsules. Acceptable capsules are collected in containerslined with double polyethylene bags and placed under desiccant.

While certain preferred and alternative embodiments of the inventionhave been set forth for purposes of disclosing the invention,modifications to the disclosed embodiments may occur to those who areskilled in the art. Accordingly, the appended claims are intended tocover all embodiments of the invention and modifications thereof whichdo not depart from the spirit and scope of the invention.

What is claimed is:
 1. A stable pharmaceutical dosage formulation fororal administration comprising a plurality of enteric coated pelletswherein each pellet consists essentially of: a) a coreconsisting-essentially of 10-50 weight percent based on the total weightof the core of omeprazole or a pharmaceutically acceptable salt thereof,a surface active agent, a filler, a binder and 0.5 to 10 weight percentbased on the total weight of the core of a pharmaceutically acceptablealkaline agent, wherein the alkaline agent is selected from the groupconsisting of lysine and arginine; and b) a coating layer surroundingthe core that consists essentially of an enteric coating agent, 5 to 50weight percent based on the total weight of the coating layer of aninert processing aid and optionally a plasticizer wherein the entericcoating layer is applied directly to the omeprazole containing corewithout a separating layer between the omeprazole containing core andenteric coating layer and wherein said pharmaceutical dosage formulationis a capsule.
 2. The pharmaceutical dosage formulation as recited inclaim 1 wherein the core consists essentially of 10 to 50 weight percentbased on the total weight of the core of omeprazole, a surface activeagent a filler, a binder and 0.5 to 10 weight percent based on the totalweight of the core of a pharmaceutically acceptable alkaline agent,wherein the alkaline agent is selected from the group consisting oflysine and arginine.
 3. The pharmaceutical dosage formulation as recitedin claim 1 wherein the core consists essentially of 10 to 50 weightpercent based on the total weight of the core of a pharmaceuticallyacceptable salt of omeprazole, a surface active agent, a filler, abinder and 0.5 to 10 weight percent based on the total weight of thecore of a pharmaceutically acceptable alkaline agent wherein thealkaline agent is selected from the group consisting of lysine andarginine.
 4. The pharmaceutical dosage formulation as recited in claim 1wherein the plasticizer in the enteric coating is not optional.
 5. Thepharmaceutical dosage formulation as recited in claim 1 wherein theenteric coating agent is selected from the group consisting of celluloseacetate phthalate, hydroxypropyl methyl cellulose phthalate, polyvinylacetate phthalate, carboxymethylethyl cellulose, co-polymerizedmethacrylic acid/methacrylic acid methyl esters.
 6. The pharmaceuticaldosage formulation as recited in claim 1 wherein the inert processingaid is selected from the group consisting of talc, silicon dioxide andmagnesium stearate.
 7. The pharmaceutical dosage formulation as recitedin claim 1 wherein the core consists essentially of 10 to 50 weightpercent based on the total weight of the core of omeprazole, 0.20 to 2.0weight percent based upon the total weight of the core of a surfaceactive agent, 20 to 90 weight percent based on the total weight of thecore of a filler, 0.1 to 10 weight percent,based on the total weight ofthe core of a binder and 1 to 3 weight percent based on the total weightof the core of a pharmaceutically acceptable alkaline agent, wherein thealkaline agent is selected from the group consisting of lysine andarginine.
 8. The pharmaceutical dosage formulation as recited in claim 1wherein the core consists essentially of 10 to 50 weight percent basedon the total weight of the core of a pharmaceutically acceptable salt ofomeprazole, 0.20 to 2.0 weight percent based upon the total weight ofthe core of a surface active agent, 20 to 90 weight percent based on thetotal weight of the core of a filler, 0.1 to 10 weight percent based onthe total weight of the core of a binder and 1 to 3 weight percent basedon the total weight of the core of a pharmaceutically acceptablealkaline agent, wherein the alkaline agent is selected from the groupconsisting of lysine and arginine.
 9. A stable pharmaceutical dosageformulation for oral administration comprising a plurality of entericcoated pellets wherein each pellet consists of essentially of: (a) acore consisting essentially of: (a) an inert core and (b) a drug layerconsisting essentially of 10-50 weight percent based on the total weightof the core of omeprazole or a pharmaceutically acceptable salt, asurface active agent, a filler, a binder and 0.5 to 10 weight percentbased on the total weight of the core of a pharmaceutically acceptablealkaline agent, wherein the alkaline agent is selected from the groupconsisting of lysine and arginine; and (b) a coating layer surroundingthe core that consists essentially of an enteric coating agent, 5 to 50weight percent based on the total weight of the coating layer of aninert processing aid and optionally a plasticizer wherein the entericcoating layer is applied directly to the omeprazole containing corewithout a separating layer between the omeprazole containing core andenteric coating layer and wherein said pharmaceutical dosage formulationis a capsule.
 10. The pharmaceutical dosage formulation as recited inclaim 9 wherein the drug layer consists essentially of 10 to 50 weightpercent based on the total weight of the core of omeprazole, a surfaceactive agent, a filler, a binder and 0.5 to 10 weight percent based onthe total weight of the core of a pharmaceutically acceptable alkalineagent, wherein the alkaline agent is selected from the group consistingof lysine and arginine.
 11. The pharmaceutical dosage formulation asrecited in claim 9 wherein the drug layer consists essentially of 10 to50 weight percent based on the total weight of the core of apharmaceutically acceptable salt of omeprazole, a surface active agent,a filler, a binder and 0.5 to 10 weight percent based on the totalweight of the core of a pharmaceutically acceptable alkaline agent,wherein the alkaline agent is selected from the group consisting oflysine and arginine.
 12. The pharmaceutical dosage formulation asrecited in claim 9 wherein the plasticizer in the enteric coating is notoptional.
 13. The pharmaceutical dosage formulation as recited in claim9 wherein the enteric coating agent is selected from the groupconsisting of cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, carboxymethylethylcellulose, co-polymerized methacrylic acid/methacrylic acid methylesters.
 14. The pharmaceutical dosage formulation as recited in claim 9wherein the inert processing aid is selected from the group consistingof talc, silicon dioxide and magnesium stearate.
 15. The pharmaceuticaldosage formulation as recited in claim 9 wherein the drug layer consistsessentially of 10 to 50 weight percent based on the total weight of thecore of omeprazole, 0.20 to 2.0 weight percent based upon the totalweight of the core of a surface active agent 20 to 90 weight percentbased on the total weight of the core of a filler, 0.1 to 10 weightpercent based on the total weight of the core of a binder and 1 to 3weight percent based on the total weight of the core of apharmaceutically acceptable alkaline agent, wherein the alkaline agentis selected from the group consisting of lysine and arginine.
 16. Thepharmaceutical dosage formulation as recited in claim 9 wherein the druglayer consists essentially of 10 to 50 weight percent based on the totalweight of the core of a pharmaceutically acceptable salt of omeprazole,0.20 to 2.0 weight percent based upon the total weight of the core of asurface active agent, 20 to 90 weight percent based on the total weightof the core of a filler, 0.1 to 10 weight percent based on the totalweight of the core of a binder and 1 to 3 weight percent based on thetotal weight of the core of a pharmaceutically acceptable alkalineagent, wherein the alkaline agent is selected from the group consistingof lysine and arginine.